Various taxane compounds are known to exhibit anti-tumor activity. As a result of this activity, taxanes have received increasing attention in the scientific and medical community. Primary among these is a compound known as "paclitaxel" which is also referred to in the literature as "taxol". Paclitaxel has been approved for the chemotherapeutic treatment of several different varieties of tumors, and the clinical trials indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity.
Paclitaxel is a naturally occurring taxane diterpenoid which is found in several species of the yew (genus Taxus, family Taxaceae). Unfortunately, the concentration of this compound is very low. The species of evergreen are also slow growing. Even though the bark of the yew trees typically exhibit the highest concentration of paclitaxel, the production of one kilogram of paclitaxel requires approximately 16,000 pounds of bark. Thus, the long term prospects for the availability of paclitaxel through isolation is discouraging.
While the presence of paclitaxel in the yew tree is in extremely low concentrations, there are a variety of other taxane compounds, such as Baccatin III, cephalomanine, 10-deacetylbaccatin III, etc., which are also able to be extracted from the yew bark. Some of these other taxane compounds are more readily extracted in higher yields. Indeed, a relatively high concentration of 10-deacetylbaccatin III can be extracted from the leaves of the yew as a renewable resource.
Among the various taxane compounds which have been found to exhibit anti-tumor activity is the compound known as "docetaxel". This compound is also sold under the trademark TAXOTERE.RTM. by Rhone-Poulenc Sante. Docetaxel has the formula as follows: ##STR2## As may be seen in this formulation, docetaxel is similar to paclitaxel except for the inclusion of the t-butoxycarbonyl (t-BOC) group at the C3' nitrogen position of the isoserine side chain and a free hydroxy group at the C10 position. Several possible syntheses of docetaxel and related compounds have been reported in the Journal of Organic Chemistry: 1986, 51, 46; 1990, 55, 1957; 1991, 56, 1681; 1991, 56, 6939; 1992, 57 4320; 1992, 57 6387; and 1993, 58, 255.
In order to successfully synthesize docetaxel, convenient access to a chiral, non-racemic side chain and an abundant natural source of a usable baccatin III backbone as well as an effective means of joining the two is necessary. However, the esterification of the side chain to the baccatin III backbone is difficult because of the hindered C13 hydroxyl in the baccatin III backbone which is located within the concave region of the hemispherical taxane skeleton. This difficulty of synthesis is present both for the synthesis of docetaxel as well as for the synthesis of paclitaxel.
One technique for the semi-synthesis of paclitaxel is found in co-pending patent application Ser. No. 08/483,081. In this application, paclitaxel is synthesized from C7 TES protected baccatin III with N-carbamate protected C2' hydroxyl-benzyl protected (2R,3S)-3-phenyl isoserine A-ring side chain with a hydrogenable benzyl-type protecting group, such as a benzyloxymethyl (BOM) protecting group at the C2' location for the side chain. Following the condensation of the C7 TES protected baccatin III and the side chain, the compound may be suitably deprotected, acylated, and further deprotected to yield paclitaxel.
While the existing techniques for synthesizing docetaxel certainly have merit, there is still a need for improved chemical processes which can produce this anti-cancer compound. The present invention is directed to such a procedure utilizing the N-carbamate protected C2' hydroxyl benzyl protected (2R,3S)-3-phenylisoserine A-ring side chain as described in my earlier co-pending application.